Tumors scavenge various nutrients for carbon and nitrogen sources required for the synthesis of biomolecules to support the growth and replication of their rapidly dividing cells. Nutrient availability plays a pivotal role in the reprogramming of tumor metabolic pathways to sustain increased energetic and anabolic demands. One of the frequent metabolic adaptations observed in different types of tumor cells is an increased uptake of glucose and aerobic glycolysis along with decreased oxidative metabolism, a phenomenon widely known as the Warburg effect (Vander Heiden, et al., 2009). However, it is well documented that tumor cells do not rely on a single metabolic-state and instead acquire a variety of strategies to adapt to alterations in nutrient availability and metabolic stress conditions during the course of disease progression (Cantor & Sabatini, 2012; Ward & Thompson, 2012). Recent studies using 13C-isotopes have identified a complimentary switch of glutamine metabolism by tumor cells to efficiently support carbon utilization for anabolism and growth (Metallo, et al., 2011; Mullen, et al., 2011). The glutamine metabolic pathway serves as a crucial source for anaplerosis of carbon atoms to balance the metabolic flux through the tricarboxylic acid cycle (TCA) cycle and to support the increased biosynthesis of macromolecules such as nucleotides and lipids, and mitochondrial ATP synthesis (Gao, et al., 2009; Wise, et al., 2008).
Unlike other solid tumors, adenocarcinoma of the prostate display very unique metabolic features since the majority of primary tumors do not show a classical ‘glycolytic switch’ and so are not efficiently detected in FDG-PET (Zadra, et al., 2013). Instead, an aberrant increase in de novo lipogenesis (Rossi, et al., 2003) coupled with glucose and glutamine metabolism is observed (Fendt, et al., 2013) in prostatic tumors from early clinical stages, and is significantly associated with poor prognosis and worse disease outcome (Menendez & Lupu, 2008). Lipids contribute to various aspects of tumor biology by functioning as building blocks for membrane biogenesis, phospholipids for membrane structure, lipid rafts for cell signaling, and more importantly for energy production and storage (Currie, et al., 2013). While most normal human cells prefer exogenous sources of fatty acids, tumor cells rely more on de novo fatty acid biosynthesis (Currie, et al., 2013) and this is true especially in prostate cancer cells. Thus, it is of utmost importance to identify the oncogenic factors that reprogram the metabolic pathways that maintain this increased lipogenic program in prostate tumors.
Previous findings identified steroid receptor coactivator-2 (SRC-2, also known as NCOA2, TIF2, GRIP 1), a potent transcriptional coregulator for nuclear receptors (NRs) and other transcription factors (Dasgupta, et al., 2013), as a critical coordinator of energy homeostasis (Chopra, et al., 2008; Chopra, et al., 2011; Picard, et al., 2002). Importantly, recent findings from ‘integrative genomic profiling’ of human prostate tumors revealed SRC-2 is a potent oncogene in ˜8% of the primary tumors, but notably, in ˜37% of the metastatic prostate tumors (Taylor, et al., 2010). Furthermore, prostate cancer patients harboring SRC-2 gene amplification or overexpression had higher rates of biochemical recurrence, and SRC-2 expression was a significant predictor of time-to-biochemical recurrence (Agoulnik, et al., 2006). These findings accentuate the clinical importance of the SRC-2 gene in prostate cancer pathology (Dasgupta, et al., 2012). Functionally, SRC-2 acts as a transcriptional coregulator of androgen receptor (AR) (Agoulnik, et al., 2006) in prostate cancer cells, however, its mode of action in aggressive metastatic prostate cancer (CRPC) is not clearly understood. Moreover none of the studies have yet investigated the functional role of SRC-2 in cancer metabolism, nor have they determined whether this recent but well-described association of SRC-2 is a critical requirement for prostate cancer cell survival and metastasis (Taylor, et al., 2010).
The present disclosure provides a solution to a long-felt need in the art to provide a marker for cancer metastasis.